Touch sensation, which is essential for our daily life, social interactions and sexual behaviors, is mediated by mechanosensory neurons within the trigeminal (TG) and dorsal root ganglion (DRG). Despite its importance, touch sensation is poorly understood in mammals. The molecular basis of mechanosensitivity, the developmental mechanisms that generate different types of mechanosensory neurons and circuits, and their unique functions, are largely unknown. Our long-term goal is to understand, at the molecular, cellular and circuit levels, the developmental mechanisms and the function of different types of mammalian mechanosensory neurons, using mice as a model system. Previously, we discovered that a small population of mouse somatosensory neurons expressing the neurotrophic receptor tyrosine kinase Ret develops into a classic type of mammalian mechanosensory neuron, the rapidly adapting (RA) mechanoreceptors. Moreover, we established a central role for Ret in controlling the development RA mechanoreceptors and found that peripheral end organs of one subtype of RA mechanoreceptors, the Pacinian corpuscles, are not formed in Ret knock-out mice. However, the signaling targets of Ret to specify different subtypes of RA mechanoreceptors remain elusive. Interestingly, our preliminary studies have identified the ETS transcription factor Er81 as an important target of Ret signaling in the specification of Pacinian corpuscle neurons. We propose to elucidate the roles of a Ret/Er81 signaling pathway in controlling the development of Pacinian corpuscle neurons. Aim I: Characterize the function of Er81 in Pacinian corpuscle and touch circuit formation. We will thoroughly characterize the expression of Er81 in RA mechanoreceptors using in situ hybridization and immunostaining at different developmental stages. We will also address the primary deficits of Er81 null Pacinian corpuscle neurons and use tissue specific knockout mice to determine if Er81 is required not only in neurons but also in accessory cells for Pacinian corpuscle formation. Lastly, we will address whether Er81 is required for maintenance of Pacinian corpuscles by ablating Er81 in adult mice. Aim II: Determine how Ret regulates Er81 to control the development of Pacinian corpuscle neurons. We will examine if Ret signaling is required and/or sufficient for regulating Er81 transcription, phosphorylation and nuclear localization in Pacinian corpuscle neurons. We will also determine if Er81 is necessary and/or sufficient for mediating the Ret signaling. Finally, we will address if Ret regulates Er81 through the mitogen- activated protein kinase (MAPK) pathway. In summary, the proposed research will determine (1) if Er81 is a novel target of Ret signaling to control the development of Pacinian corpuscle neurons and (2) how Ret signaling regulates Er81 in vivo. Results from this research will greatly improve our understanding of how mammalian mechanoreceptors develop and provide insight into axonal regeneration after injuries.